Connectors, drug connectors and conjugates thereof, and methods

Abstract

The invention provides polar units, linker intermediates, linkers, drug linkers and conjugates thereof.

Claims

1. A linker intermediate having the following formula (V), <h2 style=";text-align:left;direction:ltr">(AA)<h2 style=";text-align:left;direction:ltr"> s <h2 style=";text-align:left;direction:ltr"> -[L2]≈ (V) or a salt thereof, wherein: AA is an amino acid unit having 1 to 12 amino acid subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 attachment sites for drug units; as well as Each wavy (~) line indicates a ligation site for an extension unit; as well as The double wavy (≈) line indicates the attachment site for the drug unit, wherein at least one polar unit is present in the amino acid unit, the linker subunit, or both, and wherein the polar unit is selected from the group consisting of a sugar unit, a PEG unit, a carboxyl unit, and combinations thereof.

2. A linker having the following formula (I), ~L1-(AA) s -L2≈ (I) or a salt thereof, wherein: L1 is an extension unit with a connection site for a targeting unit; AA is an amino acid unit having 1 to 12 subunits; s is 0 or 1; L2 is a linker subunit having 1 to 4 attachment sites for drug units; The wavy (~) line indicates the attachment site for the targeting unit; and The double wavy (≈) line indicates the attachment site for the Drug unit; Wherein at least one polar unit is present in the amino acid unit, the linker subunit, the extender unit or a combination thereof, and wherein the polar unit is selected from the group consisting of a sugar unit, a PEG unit, a carboxyl unit and a combination thereof.

3. A linker intermediate or linker according to any preceding claim, wherein the sugar unit has the formula: <h2 style=";text-align:left;direction:ltr">L3-**N(CH2-(CH(XR))<h2 style=";text-align:left;direction:ltr"> k <h2 style=";text-align:left;direction:ltr"> -X1(X2))2 (X) or a salt thereof, wherein: Each X is independently selected from NH or O; Each R is independently selected from hydrogen, acetyl, monosaccharide, disaccharide and polysaccharide; Each X1 is independently selected from CH2 and C(O); Each X2 is independently selected from H, OH and OR; k is 1 to 10; and L3 has the following general formula (XI): or a salt thereof, wherein: L3a is selected from C1-C 10 Alkylene and polyethylene glycol having 1 to 24 ethylene glycol subunits; p and o are independently 0 to 2; Each * and each # represent a connection site for an amino acid unit (AA), a linker subunit L2, or other subunits of an extension unit (L1); and L3a is covalently bonded to the N atom marked with ** in formula (X).

4. A linker intermediate or linker as claimed in any one of the preceding claims, wherein the sugar unit has a formula selected from the following: or or a salt thereof, wherein: Each R is independently selected from hydrogen, a monosaccharide, a disaccharide, and a polysaccharide; p and o are independently 0 to 2; m is 1 to 8; n is 0 to 4; and Each * and each # represent a connection site for the amino acid unit (AA), the linker subunit L2 or other subunits of the extension unit (L1).

5. A linker intermediate or linker as claimed in any one of the preceding claims, wherein the PEG unit has a formula selected from the group consisting of: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) or a salt thereof, wherein: R 20 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 21 and R 22 Each is independently a C1-C3 alkylene group selected as appropriate; R 24 and R 25 Each is independently selected from H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C3-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 carbocyclic ring; optionally substituted heteroaryl; optionally substituted carbocyclic ring; substituted -C1-C8 alkyl; substituted -C(O)-C1-C8 alkyl; chelate; -C(O)-R 28 , where R 28 is a sugar unit of formula (XII) or formula (XIII); or with -NR 24 R 25 Together they form a C3-C8 heterocycle; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; or (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NR 24 R 25 (XX) or a salt thereof, wherein: R 20 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 21 and R 22 Each is independently a C1-C3 alkylene group selected as appropriate; R 24 and R 25 One of them is selected from H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C3-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 carbocyclic ring; optionally substituted heteroaryl; optionally substituted carbocyclic ring; substituted -C1-C8 alkyl; substituted -C(O)-C1-C8 alkyl; chelate; -C(O)-R 28 , where R 28 is a sugar unit of formula (XII) or formula (XIII); and R 24 and R 25 The other of is polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; or (c) ~R 20 -[-R 26 -[R 29 -[O-CH2-CH2-] n20 R 29 ] n21 -R 27 -] n27 -NR 24 R 25 (XXI) or a salt thereof, wherein: R 20 is a functional group for connecting to a subunit of an amino acid unit and / or a part of the linker subunit L2; R 26 and R 27 Each is optionally and independently selected from C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C12 alkylene-NH-, -C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)- and -C(O)-C1-C 12 Alkylene -NH-; R 24 and R 25 One of them is selected from H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C3-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 carbocyclic ring; optionally substituted heteroaryl; optionally substituted carbocyclic ring; substituted -C1-C8 alkyl; substituted -C(O)-C1-C8 alkyl; chelate; -C(O)-R 28 , where R 28 is a sugar unit of formula (XII) or formula (XIII); and R 24 and R 25 The other of is selected from H; a polyhydroxyl group; a substituted polyhydroxyl group; a -C(O)-polyhydroxyl group; a substituted -C(O)-polyhydroxyl group; an optionally substituted C3-C 10 Carbocyclic ring; optionally substituted C1-C3 alkylene C3-C 10 carbocyclic ring; optionally substituted heteroaryl; optionally substituted carbocyclic ring; substituted -C1-C8 alkyl; substituted -C(O)-C1-C8 alkyl; chelate; -C(O)-R 28 , where R 28 is a sugar unit of formula (XII) or formula (XIII); and polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits; or with -NR 24 R 25 Together they form a C3-C8 heterocycle; Each R 29 Optionally and independently selected from -C(O)-, -NH-, -C(O)-C1-C6 alkenylene-, -NH-C1-C6 alkenylene-, -C1-C6 alkenylene-NH-, -C1-C6 alkenylene-C(O)-, -NH(CO)NH- and triazole; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; n21 is 1 to 4; and n27 is 1 to 4.

6. The linker intermediate or linker as claimed in claim 5, wherein R 24 and R 25 None of them is H.

7. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 Each independently selected from H and polyhydroxy groups, with the restriction that R 24 and R 25 Not all are H.

8. A linker intermediate or linker as claimed in any one of claims 5 to 7, wherein the polyhydroxyl group is a linear monosaccharide, optionally selected from C6 or C5 sugars, sugar acids or amino sugars.

9. The linker intermediate or linker according to claim 8, wherein: the C6 or C5 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idose, talose, aldose and ketose; The sugar acid is selected from gluconic acid, aldonic acid, uronic acid and ulosonic acid; or The amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine and N-acetylgalactosamine.

10. The linker intermediate or linker according to any one of claims 5 to 9, wherein the PEG unit is selected from the following, or a salt thereof: Where R 39 is selected from H, a linear monosaccharide and polyethylene glycol, optionally having 1 to 24 ethylene glycol subunits; and the wavy line on the left represents the site of attachment to a subunit of the amino acid unit or a portion of the linker subunit.

11. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 One of them is a linear monosaccharide and the other is a cyclic monosaccharide.

12. The linker intermediate or linker of claim 11, wherein the PEG unit is selected from the following, or a salt thereof: Where R 41 is a cyclic monosaccharide; and the wavy line on the left represents the attachment site to a subunit of the amino acid unit or a part of the linker subunit.

13. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 Independently selected from cyclic monosaccharides, disaccharides and polysaccharides.

14. The linker intermediate or linker of claim 13, wherein the PEG unit is selected from the following, or a salt thereof: Among them, each R 45 is selected from H and a monosaccharide, a disaccharide or a polysaccharide; and R 46 is selected from cyclic monosaccharides, disaccharides or polysaccharides; and the wavy line on the right represents the site of attachment to the subunit of the amino acid unit or a part of the linker subunit.

15. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 Independently selected from linear monosaccharides and substituted linear monosaccharides, wherein the substituted linear monosaccharides are substituted with monosaccharides, disaccharides or polysaccharides.

16. The linker intermediate or linker of claim 15, wherein the PEG unit is selected from the following, or a salt thereof: Where R 47 is a linear monosaccharide; and each R 49 is selected from the group consisting of a monosaccharide, a disaccharide and a polysaccharide; and the wavy line on the left represents a site of attachment to a subunit of the amino acid unit or a portion of the linker subunit.

17. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 Independently selected from linear monosaccharides and substituted monosaccharides, wherein the substituted linear monosaccharides are substituted with one or more substituents selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester or amide, and are further substituted with monosaccharides, disaccharides or polysaccharides as appropriate.

18. The linker intermediate or linker of claim 17, wherein the PEG unit is selected from the following, or a salt thereof: or Among them, each R 42 are independently selected from linear monosaccharides and substituted linear monosaccharides; each R 43 are independently selected from alkyl, O-alkyl, aryl, O-aryl, carboxyl, ester and amide; and the wavy line on the left represents the connection site to the subunit of the amino acid unit or a part of the linker subunit.

19. The linker intermediate or linker according to any one of claims 5 to 6, wherein R 24 and R 25 One of them is a -C(O)-polyhydroxy group or a substituted -C(O)-polyhydroxy group, and R 24 and R 25 The other of is H, -C(O)-polyhydroxy, substituted -C(O)-polyhydroxy, polyhydroxy or substituted polyhydroxy; wherein the substituted -C(O)-polyhydroxy and polyhydroxy are substituted with a monosaccharide, a disaccharide, a polysaccharide, an alkyl, -O-alkyl, an aryl, a carboxyl, an ester or an amide.

20. The linker intermediate or linker of claim 19, wherein the PEG unit is selected from the following, or a salt thereof: The wavy line on the left side indicates the connection site with the subunit of the amino acid unit or a part of the linker subunit.

21. A linker intermediate or linker as claimed in any one of claims 5 to 6, wherein R 24 and R 25 is independently selected from H, substituted -C1-C8 alkyl, substituted -C1-C4 alkyl or substituted -C1-C3 alkyl; with the limitation that R 24 and R 25 wherein the substituted -C1-C8 alkyl, -C1-C4 alkyl and -C1-C3 alkyl are substituted by hydroxyl and / or carboxyl.

22. The linker intermediate or linker of claim 21, wherein the PEG unit is selected from the following, or a salt thereof: Where R 48 is selected from H, OH, CH2OH, COOH or a -C1-C6 alkyl group substituted with a hydroxyl group or a carboxyl group; and the wavy line on the left represents the connection site with a subunit of the amino acid unit or a part of the linker subunit.

23. A linker intermediate or linker as claimed in any one of claims 5 to 6, wherein R 24 and R 25 One of them is selected from H, substituted -C(O)-C1-C8 alkyl, substituted -C(O)-C1-C4 alkyl and substituted -C(O)-C1-C3 alkyl, and R 24 and R 25 The other one is selected from substituted -C(O)-C1-C8 alkyl, substituted -C(O)-C1-C4 alkyl, substituted -C(O)-C1-C3 alkyl, substituted -C1-C8 alkyl, substituted -C1-C4 alkyl and substituted -C1-C3 alkyl, wherein substituted -C(O)-C1-C8 alkyl, substituted -C(O)-C1-C4 alkyl, substituted -C(O)-C1-C3 alkyl, substituted -C1-C8 alkyl, -C1-C4 alkyl and -C1-C3 alkyl are substituted with hydroxyl and / or carboxyl.

24. The linker intermediate or linker of claim 23, wherein the PEG unit is selected from the following, or a salt thereof: The wavy line on the left side indicates the connection site with the subunit of the amino acid unit or a part of the linker subunit.

25. A linker intermediate or linker as claimed in any one of claims 5 to 6, wherein R 24 and R 25 is selected from H and optionally substituted aryl; with the proviso that R 24 and R 25 None of them is H.

26. The linker intermediate or linker of claim 25, wherein the PEG unit is selected from the following, or a salt thereof: The wavy line on the left side indicates the attachment site for the subunit of the amino acid unit or a part of the linker subunit.

27. A linker intermediate or linker as claimed in any one of claims 5 to 6, wherein R 24 and R 25 Together they form an optionally substituted C3-C8 heterocycle or heteroaryl.

28. The linker intermediate or linker of claim 27, wherein the PEG unit is: or a salt thereof.

29. A linker intermediate or linker as claimed in any one of claims 5 to 6, wherein R 24 and R 25 independently selected from H and a chelate, wherein the chelate is optionally attached to -NR via an alkylene, arylene, carbocyclic, heteroarylene or heterocarbocyclic ring. 24 R 25 of nitrogen; the limiting condition is R 24 and R 25 None of them is H.

30. The linker intermediate or linker of claim 29, wherein the chelate is selected from ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), triethylenetetraaminehexaacetic acid (TTHA), benzyl-DTPA, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), benzyl-DOTA, 1,4,7-triazacyclononane-N,N',N"-triacetic acid (NOTA), benzyl-NOTA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and N,N'-dialkyl substituted piperazine.

31. The linker intermediate or linker of claim 30, wherein the PEG unit is selected from the following, or a salt thereof: The wavy line on the left side indicates the connection site with the subunit of the amino acid unit or a part of the linker subunit.

32. The linker intermediate or linker of any one of claims 5 to 19, wherein each monosaccharide is independently selected from: C5 or C6 sugar, wherein the C5 or C6 sugar is selected from glucose, ribose, galactose, mannose, arabinose, 2-deoxyglucose, glyceraldehyde, erythrose, threose, xylose, lyxose, allose, altrose, gulose, idose, talose, aldose, ketose, glucosamine, N-acetylglucosamine, galactosamine and N-acetylgalactosamine; A sugar acid selected from the group consisting of gluconic acid, aldonic acid, uronic acid and ketonic acid; or Amino sugar, wherein the amino sugar is selected from glucosamine, N-acetylglucosamine, galactosamine and N-acetylgalactosamine.

33. A linker intermediate or linker as claimed in any one of claims 5 to 32, wherein R 20 is selected from halide, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl or protected forms thereof.

34. The linker intermediate or linker of any one of claims 1 to 4, wherein the PEG unit has a formula selected from: (a) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -R 30 (XXX) or a salt thereof, wherein: R 20 is a functional group for linking to a subunit of the Amino Acid unit (if present) and / or a portion of the Linker subunit L2; R 21 and R 22 each optionally and, if present, independently a C1-C3 alkylene group; R 30 is selected from optionally substituted C3-C 10 carbocycle; thiourea; optionally substituted thiourea; urea; optionally substituted urea; sulfonamide; alkylsulfonamide; acylsulfonamide, optionally substituted alkylsulfonamide; optionally substituted acylsulfonamide; sulfonamide; optionally substituted sulfonamide; guanidine, including alkylguanidine and arylguanidine; phosphoramide; or optionally substituted phosphoramide; or R 30 is selected from azido, alkynyl, substituted alkynyl, -NH-C(O)-alkynyl, -NH-C(O)-alkynyl-R 65 ; Cyclooctyne; -NH-cyclooctyne, -NH-C(O)-cyclooctyne or -NH-(cyclooctyne)2; wherein R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; (b) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI) or a salt thereof, wherein: R 20 is a functional group used to link to the subunit of the Amino Acid unit (if present) or a part of the Linker subunit L2; R 21 and R 22 Each is independently a C1-C3 alkylene group selected as appropriate; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having R at its end 35 ; R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , where R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; (c) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII) or a salt thereof, wherein: R 20 is a functional group used to link to the subunit of the Amino Acid unit (if present) or a part of the Linker subunit L2; R 21 and R 22 Each is optionally and independently a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch independently having 1 to 26 ethylene glycol subunits, and each branch having R at its end 35 ; R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , where R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle, and optionally substituted heteroaryl; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26; and (d) ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII) or a salt thereof, wherein: R 20 is a functional group used to link to the subunit of the Amino Acid unit (if present) or a part of the Linker subunit L2; R 21 and R 22 Each is optionally a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having R at its end 35 ; R 33 is C1-C3 alkylene, -C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene or -C(O)-C1-C3 alkylene-C(O); R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , where R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; The wavy line (~) indicates 20 The attachment site of n20 is 1 to 26.

35. The linker intermediate or linker of any one of claims 1 to 4, wherein the PEG unit has a formula selected from the following, or a salt thereof: ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -NH-C(O)-R 31 (XXXI), ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -C(O)NH-R 31 (XXXII), or ~R 20 -R 21 -[O-CH2-CH2] n20 -R 22 -N-(R 33 -R 31 )2 (XXXIII); Where R 20 is a functional group for linking to the subunit of the Amino Acid unit (if present) or a part of the Linker subunit L2; R 21 and R 22 Each is optionally a C1-C3 alkylene group; R 31 is a branched polyethylene glycol chain, each branch having 1 to 26 ethylene glycol subunits, and each branch having R at its end 35 ; R 33 is C1-C3 alkylene, -C1-C3 alkylene-C(O), -C(O)-C1-C3 alkylene or -C(O)-C1-C3 alkylene-C(O); R 35 is azido, alkynyl, alkynyl-R 65 , cyclooctyne or cyclooctyne-R 65 , where R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; the wavy (~) line represents the residue with R 20 The attachment site of and n20 is 1 to 26.

36. The linker intermediate or linker of claim 35, wherein the PEG unit is selected from the group consisting of: Where R 65 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocycle, optionally substituted aryl, optionally substituted heterocarbocycle or optionally substituted heteroaryl; and the wavy line on the left represents the site of attachment to a subunit of the Amino Acid unit or a portion of the Linker subunit.

37. A linker intermediate or linker as claimed in any one of claims 34 to 36, wherein R 20 is selected from halide, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl or protected forms thereof.

38. The linker intermediate or linker of claims 1 to 4, comprising a PEG unit having a formula selected from: ~R 40 -(R 43 -R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XL) or a salt thereof, wherein: R 40 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 41 and R 42 Not present or each independently represents a C1-C6 alkylene group; Each R 43 Independently absent or selected from C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene, heteroaryl-C1-C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 , where R 46 and R 47 One of them is H or C1-C 12 alkylene and the other is C1-C 12 Alkylene; R 44 and R 45 are each independently H, a polyhydroxy group, a substituted polyhydroxy group, a -C(O)-polyhydroxy group, or a substituted -C(O)-polyhydroxy group, wherein the substituents are optionally selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) indicates 40 The attachment site of n40 is 1 to 26; n41 is 1 to 6; as well as n42 is 1 to 6.

39. The linker intermediate or linker of claims 1 to 4, comprising a PEG unit having a formula selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLI) or a salt thereof, wherein: R 40 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 41 and R 42 Not present or each independently represents a C1-C6 alkylene group; R 43 Not present or selected from C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene, heteroaryl-C1-C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 , where R 46 and R 47 One of them is H or C1-C 12 an alkylene group, and The other is C1-C 12 Alkylene; R 44 and R 45 are each independently H, a polyhydroxy group, a substituted polyhydroxy group, a -C(O)-polyhydroxy group, or a substituted -C(O)-polyhydroxy group, wherein the substituents are optionally selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) indicates 40 The attachment site of n40 is 1 to 26; n41 is 1 to 6; as well as n42 is 1 to 6.

40. The linker intermediate or linker of claims 1 to 4, comprising a PEG unit having a formula selected from: ~R 40 -(R 41 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLII) or a salt thereof, wherein: R 40 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 41 and R 42 Not present or each independently represents a C1-C3 alkylene group; R 43 Not present or selected from C1-C6 alkylene, -NH-C1-C 12 Alkylene, -C1-C6 alkylene-NH-, -C(O)-C1-C6 alkylene, -C1-C6 alkylene-C(O)-, -NH-C1-C6 alkylene-C(O)-, -C(O)-C1-C6 alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C6 alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C6 alkylene, heteroaryl-C1-C6 alkylene-C(O)- or -C(O)NR 46 R 47 , where R 46 and R 47 One of them is H or C1-C6 alkylene, and the other is C1-C 12 Alkylene; R 44 and R 45 are each independently H, a polyhydroxy group, a substituted polyhydroxy group, a -C(O)-polyhydroxy group, or a substituted -C(O)-polyhydroxy group, wherein the substituents are optionally selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; The wavy line (~) indicates 40 The attachment site of n40 is 1 to 16; n41 is 1 to 4; as well as n42 is 1 to 4.

41. A linker intermediate or linker as claimed in any one of claims 38 to 40, wherein R 40 is selected from halogen, aldehyde, carboxyl, amino, alkynyl, azido, hydroxyl, carbonyl, carbamate, thiol, urea, thiocarbamate, thiourea, sulfonamide, acylsulfonamide, alkylsulfonate, triazole, azadibenzocyclooctyne, hydrazine, carbonylalkylheteroaryl or protected forms thereof.

42. A linker intermediate or linker as claimed in any one of claims 38 to 40, wherein R 40 Has one of the following structures: Where R=H or C 1-6 Alkyl; and n=0 to 12 or its stereoisomers, wherein (*) represents R 40 a site of attachment to a subunit of the amino acid unit or a portion of the linker subunit L2, and Represents R 40 The site of attachment to the rest of the PEG unit.

43. A linker intermediate or linker as claimed in claims to 42, wherein R 40 Has one of the following structures: Where n = 0 to 12 or its stereoisomers, wherein (*) represents R 40 a site of attachment to a subunit of the amino acid unit or a portion of the linker subunit L2, and Represents R 40 The site of attachment to the rest of the PEG unit.

44. A linker intermediate or linker as described in claims 38 to 40, wherein R 43 -(NR 44 R 45 ) n41 When there is NR 43 has one of the following structures: Where R=H、C 1-6 Alkyl, polyhydroxy or substituted polyhydroxy or a stereoisomer thereof, wherein Represents R 43 The site of attachment to the rest of the PEG unit.

45. The linker intermediate or linker of claim 44, wherein R 43 -(NR 44 R 45 ) n41 When there is NR 43 has one of the following structures: or a stereoisomer thereof, wherein Represents R 43 The site of attachment to the rest of the PEG unit.

46. ​​A linker intermediate or linker as claimed in any one of claims 38 to 44, wherein -NR 44 R 45 Has one of the following structures: or a stereoisomer thereof, wherein Indicates -NR 44 R 45 The site of attachment to the rest of the PEG unit.

47. A linker intermediate or linker as claimed in any one of the preceding claims, wherein the PEG unit has one of the following structures prior to being linked to the Amino Acid unit or a portion of the Linker Subunit L2: wherein R is H or alkyl, and n is 1 to 12.

48. The linker intermediate or linker of claims 1 to 4, comprising a PEG unit having a formula selected from: ~R 40 -(R 43 -R 41 --[O-CH2-CH2] n40 -R 46 -[O-CH2-CH2] n40 -R 42 -R 43 -(NR 44 R 45 ) n41 ) n42 (XLIII) or a salt thereof, wherein: R 40 is a functional group for connecting to a subunit of the amino acid unit or a part of the linker subunit L2; R 41 and R 42 Not present or each independently represents a C1-C6 alkylene group; Each R 43 Independently absent or selected from C1-C 12 Alkylene, -NH-C1-C 12 Alkylene, -C1-C 12 Alkylene-NH-, -C(O)-C1-C 12 Alkylene, -C1-C 12 Alkylene-C(O)-, -NH-C1-C 12 Alkylene-C(O)-, -C(O)-C1-C 12 Alkylene-NH-, -NH-C(O)-NH-, -NH-C(O)-, -NH-C(O)-C1-C 12 Alkylene, -C(O)-NH-C1-C 12 Alkylene, -heteroarylene, heteroaryl-C1-C 12 Alkylene, heteroaryl-C1-C 12 Alkylene-C(O)- or -C(O)NR 46 R 47 , where R 46 and R 47 One of them is H or C1-C 12 alkylene and the other is C1-C 12 Alkylene; R 44 and R 45 are each independently H, a polyhydroxy group, a substituted polyhydroxy group, a -C(O)-polyhydroxy group, or a substituted -C(O)-polyhydroxy group, wherein the substituents are optionally selected from sulfates, phosphates, alkyl sulfates, and alkyl phosphates; R 46 Selected from amino, amino-alkyl-amino or -NH-C(O)-NH-S(O)2-NH-; The wavy line (~) indicates 40 The attachment site of n40 is 1 to 26; n41 is 1 to 6; as well as n42 is 1 to 6.

49. A linker intermediate or linker as described in claim 48, wherein the PEG unit has one of the following structures before being linked to the Amino Acid unit or a portion of the Linker Subunit L2: wherein R is H or alkyl, and n is 1 to 12.

50. The linker intermediate or linker of claims 1 to 4, comprising a PEG unit having a formula selected from: or a salt thereof, wherein: Each Y is independently R 76 or Each R 76 are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v -OS(=O)2(OH); Each R a and R b are independently H, or R a and R b Together with the carbon to which it is attached, it forms a pendant oxygen group; Each q is independently 1 to 26; Each m is independently 1 to 4; Each n is independently 1 to 4; each v is independently 1 to 6; and Each * represents a connection site for the subunits of the Amino Acid Unit (AA), the Linker Subunit L2 or the Extender Unit (L1).

51. The linker intermediate or linker of claim 50, comprising a PEG unit having a formula selected from: or a salt thereof, wherein: Each R 76 are independently H, acetyl, -P(=O)(OH)2 or -(CH2) v S(=O)2(OH); Each q is independently 1 to 26; Each m is independently 1 to 4; Each n is independently 1 to 4; each v is independently 1 to 6; and Each * represents a connection site for the subunits of the Amino Acid Unit (AA), the Linker Subunit L2 or the Extender Unit (L1).

52. The linker intermediate or linker of claim 50 or 51, comprising a PEG unit having a formula selected from: or a salt thereof, wherein: Each q is independently 1 to 26; Each m is independently 1 to 4; each n is independently 1 to 4; and Each * represents a connection site for the subunits of the Amino Acid Unit (AA), the Linker Subunit L2 or the Extender Unit (L1).

53. The linker intermediate or linker of claim 50, wherein Y is R 76 .

54. The linker intermediate or linker of claim 50, wherein Y is 55. The linker intermediate or linker of claim 50, wherein each R a and R b is independently H.

56. The linker intermediate or linker of claim 50, wherein R a and R b Together with the carbon to which it is attached it forms a pendant oxygen group.

57. A linker intermediate or linker as described in any one of claims 50 to 52, wherein q is 10 to 20.

58. A linker intermediate or linker as described in any one of claims 50 to 52, wherein q is 12.

59. The linker intermediate or linker of any one of claims 1 to 4, 38 to 40, or 50 to 52, wherein the PEG unit is selected from the following, or a salt thereof: as well as Wherein each Z is connected at * and is selected from: as well as Among them represents the attachment site for the Amino Acid unit (AA), the Linker subunit L2 or other subunits of the Extender unit (L1).

60. The linker intermediate or linker of any one of claims 1 to 4, wherein the carboxyl unit has the formula: or a salt thereof, wherein: (a) L 70 Selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene- and -C(O)-C1-C8 alkylene-C(O)-; R 70 For NR 71 (R 72 -R 73 ), where R 71 Selected from H, C1-C 12 Alkyl, substituted C1-C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 72 is absent or is selected from optionally substituted C1-C3 alkylene, optionally substituted ether, optionally substituted thioether, optionally substituted ketone, optionally substituted amide, polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), optionally substituted carbocycle, optionally substituted aryl or optionally substituted heteroaryl, and R 73 is carboxyl or polycarboxyl, wherein the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide; Each wavy line (-) indicates a connection site for the amino acid unit (AA), the linker subunit L2 or other subunits of the extension unit (L1); and p1 and o1 are independently selected from 0 to 2; or (b) L 70 Selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene- and -C(O)-C1-C8 alkylene-C(O)-; R 70 For NR 71 (R 75 -(R 73 )2), where R 71 Selected from H, C1-C 12 Alkyl, substituted C1-C 12 alkyl or polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), R 75 is a branched optionally substituted C1-C3 alkylene, an optionally substituted ether, an optionally substituted thioether, an optionally substituted ketone, an optionally substituted amide, a polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), an optionally substituted carbocycle, an optionally substituted aryl or an optionally substituted heteroaryl, and each R 73 is independently carboxyl or polycarboxyl, wherein the polycarboxyl comprises 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide; Each wavy line (-) indicates a connection site for the amino acid unit (AA), the linker subunit L2 or other subunits of the extension unit (L1); and Each of p1 and o1 is independently selected from 0 to 2; or (c) L 70 Selected from C1-C8 alkylene, C1-C8 alkylene-C(O)-, -C(O)-C1-C8 alkylene- and -C(O)-C1-C8 alkylene-C(O)-; R 70 is ~N(R 74 -R 73 )(R 72 -R 73 ), where R 72 and R 74 are each independently selected from an optionally substituted C1-C3 alkylene, an optionally substituted ether, an optionally substituted thioether, an optionally substituted ketone, an optionally substituted amide, a polyethylene glycol (optionally having 1 to 12 ethylene glycol subunits), an optionally substituted carbocycle, an optionally substituted aryl or an optionally substituted heteroaryl, and each R 73 is independently carboxyl or polycarboxyl, comprising 1 to 10, or 1 to 6, or 1 to 4 carboxyl groups, wherein the carboxyl groups are interconnected by alkyl, alkylene, substituted alkyl, substituted alkylene, heteroalkyl, heteroalkylene, amino and / or amide; Each wavy line (-) indicates a connection site for an amino acid unit (AA), the linker subunit L2, or other subunits of the extender unit (L1); and p1 and o1 are independently selected from 0 to 2.

61. A linker intermediate or linker as claimed in any one of claims 1 to 60 comprising at least one sugar unit.

62. The linker intermediate or linker of any one of claims 1 to 60, comprising at least one PEG unit.

63. A linker intermediate or linker as described in any one of claims 1 to 60, comprising at least one carboxyl unit.

64. The linker intermediate or linker of any one of claims 1 to 60, comprising at least two polar units, each polar unit being selected from a sugar unit, a PEG unit and a carboxyl unit.

65. The linker intermediate or linker of any one of claims 1 to 60, comprising at least one sugar unit and a PEG unit or a carboxyl unit.

66. The linker intermediate or linker of any one of claims 1 to 60, comprising at least one carboxyl unit and a PEG unit.

67. A linker intermediate or linker as claimed in any one of claims 1 to 60, wherein the amino acid unit (AA) (s=1) is present.

68. A linker intermediate or linker as described in any one of claims 1 to 67, wherein the Amino Acid unit comprises at least one polar unit.

69. The linker intermediate or linker of any one of claims 1 to 68, wherein L2 or AA-L2 has one of the following structures: The wavy line on the amino group indicates the attachment site for the Extender unit, and the Drug unit is attached to the benzyl alcohol.

70. The linker intermediate or linker of any one of claims 1 to 67, wherein ~AA-L2~ has a formula selected from: ~[SU-aa]-L2≈, ~[aa1(PEG)-aa]-L2≈, or ~[CU-aa]-L2≈ wherein the square brackets represent the amino acid unit, each aa is an optionally selected subunit of AA, L2 is the linker subunit, each wavy line (~) represents a connection site for an extended unit; aa1(PEG) is a PEG unit connected to an amino acid subunit of AA, SU is a sugar unit connected to a subunit of AA or a sugar unit connected to L2, and CU is a carboxyl unit connected to a subunit of AA or a carboxyl unit connected to L2; and a double wavy (≈) line represents a connection site for a drug unit, wherein aa and aa1 are independently selected from α, β and γ amino acids and their derivatives.

71. The linker intermediate or linker of any one of claims 1 to 67, wherein ~AA-L2~ has a formula selected from: Wherein the square brackets represent the amino acid units, each aa is an amino acid subunit of AA, L2 is the linker subunit connected to the side chain of aa, and the wavy line (~) represents the connection site for the extension unit; aa1(PEG) is a PEG unit connected to aa, SU is a sugar unit connected to aa, CU is a carboxyl unit connected to aa, and the double wavy (≈) line represents the connection site for the drug unit; wherein aa and aa1 are independently selected from α, β and γ amino acids and their derivatives.

72. The linker intermediate or linker of any one of claims 1 to 68, wherein the Amino Acid unit comprises at least two polar units.

73. The linker intermediate or linker of claim 72, wherein ~AA-L2~ has a formula selected from the group consisting of: ~[SU-aa-SU]-L2≈, ~[aa1(PEG)-aa-aa2(PEG)]-L2≈, or ~[CU-aa-CU]-L2≈ Wherein the square brackets represent the amino acid unit, aa is an optionally selected subunit of AA, L2 is the linker subunit, and the wavy line (~) represents the connection site for the extended unit; aa1(PEG) and aa2(PEG) are PEG units connected to aa or PEG units connected to other PEG units, respectively; each SU is a sugar unit connected to aa or a sugar unit connected to other sugar units, each CU is a carboxyl unit connected to aa or a carboxyl unit connected to other carboxyl units, and the double wavy (≈) line represents the connection site for the drug unit; wherein aa, aa1 and aa2 are independently selected from α, β and γ amino acids and their derivatives.

74. The linker intermediate or linker of claim 72, wherein ~AA-L2~ has a formula selected from the group consisting of: Wherein the square brackets represent the amino acid unit, aa is the amino acid subunit of AA, L2 is the linker subunit connected to the side chain of aa, each wavy line (~) represents a connection site for the extended unit; aa1 (PEG) and aa2 (PEG) are PEG units connected to aa, respectively, each SU is a sugar unit connected to aa; each CU is a carboxyl unit connected to aa; and the double wavy (≈) line represents a connection site for the drug unit; wherein aa, aa1 and aa2 are independently selected from α, β and γ amino acids and their derivatives.

75. A linker intermediate or linker as claimed in any one of the preceding claims, wherein linker subunit L2 is a cleavable linker unit.

76. A linker intermediate or linker as described in claim 75, wherein the linker subunit L2 comprises a peptide that can be cleaved by an intracellular protease.

77. A linker intermediate or linker as described in claim 76, wherein the cleavable peptide comprises a valine-citrulline peptide, a valine-alanine peptide, a valine-lysine peptide, a phenylalanine-lysine peptide or a glycine-glycine-phenylalanine-glycine peptide.

78. A linker intermediate or linker as claimed in any preceding claim, wherein the linker subunit L2 comprises at least one polar unit.

79. A linker intermediate or linker as claimed in any one of the preceding claims, wherein the polar unit is a sugar unit (SU).

80. A linker intermediate or linker as described in claim 79, wherein the cleavable peptide comprises a SU-valine-citrulline peptide, a SU-valine-lysine peptide, a SU-valine-alanine peptide, a SU-phenylalanine-lysine peptide, or a SU-glycine-glycine-phenylalanine-glycine peptide.

81. A linker intermediate or linker as described in claim 78, wherein the polar unit is a carboxyl unit (CU).

82. A linker intermediate or linker as described in claim 81, wherein the cleavable peptide comprises a CU-valine-citrulline peptide, a CU-valine-lysine peptide, a valine-(CU-lysine) peptide, a CU-valine-alanine peptide, a CU-phenylalanine-lysine peptide, a phenylalanine-(CU-lysine) peptide or a CU-glycine-glycine-phenylalanine-glycine peptide, wherein CU-lysine is a carboxyl unit comprising a lysine residue.

83. A linker intermediate or linker as described in claim 78, wherein the polar unit is a PEG unit (PEG).

84. A linker intermediate or linker as described in claim 83, wherein the cleavable peptide comprises a Lys(PEG)-valine-citrulline peptide, a valine-Cit(PEG) peptide, a Lys(PEG)-valine-lysine peptide, a valine-lysine(PEG) peptide, a Lys(PEG)-valine-alanine peptide, a Lys(PEG)-phenylalanine-lysine peptide, a phenylalanine-Lys(PEG) peptide, or a Lys(PEG)-glycine-glycine-phenylalanine-glycine peptide, wherein Lys(PEG) and Cit(PEG) comprise a PEG unit attached to a lysine residue or a citrulline residue, respectively.

85. A linker intermediate or linker as claimed in any one of claims 75 to 84, wherein the cleavable peptide is linked to a p-aminobenzyl alcohol self immolative group (PABA).

86. The linker intermediate or linker of claim 85, wherein ~AA-L2≈ has one of the following structures: The wavy line on the amino group indicates the attachment site for the Extender unit, and the Drug unit is attached to the benzyl alcohol.

87. The linker intermediate or linker of any one of claims 1 to 2, wherein ~AA-L2~ has one of the following structures: Wherein each Z is connected at * and is selected from: as well as Wherein the wavy line on the amino group indicates the attachment site for the Extender unit, and the Drug unit is attached to the benzyl alcohol (ie, the H of the benzyl alcohol is replaced with a bond to the Drug unit).

88. A linker intermediate or linker as described in any one of claims 75 to 85, wherein L2 is connected to the side chain of a subunit of AA.

89. The linker intermediate or linker of claim 88, wherein ~AA-L2≈ has one of the following structures: or Wherein the wavy line on the amino group indicates the attachment site for the Extender unit and the Drug unit is attached to the terminal acid group, the benzyl alcohol, or wherein the wavy (≈) line indicates the attachment site for the Drug unit.

90. The linker intermediate or linker of any one of claims 1 to 85, wherein the amino acid unit is linked to the linker subunit L2 via a non-peptide linking group.

91. The linker intermediate or linker of claim 90, wherein the non-peptide linking group is selected from the group consisting of C1-C 10 Alkylene, C2-C 10 Alkenyl, C2-C 10 Alkyne or polyethylene glycol.

92. The Linker Intermediate of any of the preceding claims, further comprising an Extender unit.

93. The linker of claim 92, wherein the extension unit is selected from the group consisting of: Where R 17 C1-C 10 Alkylene-, -C1-C 10 Heteroalkylene-, -C3-C8 carbocyclic ring-, -O-(C1-C8 alkylene)-, -(CH2-O-CH2) b -C1-C8 alkylene-(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-(wherein b is 1 to 26), -arylene-, -C1-C 10 Alkylene-Arylene-, -Arylene-C1-C 10 Alkylene-, -C1-C 10 Alkylene-(C3-C8 carbocyclic ring)-, -(C3-C8 carbocyclic ring)-C1-C 10 Alkylene-, -C3-C8 heterocyclic-, -C1-C 10 Alkylene-(C3-C8 heterocycle)-, -(C3-C8 heterocycle)-C1-C 10 Alkylene-, -C1-C 10 Alkylene-C(=O)-, C1-C 10 Heteroalkylene-C(=O)-, -C1-C8alkylene-(CH2-O-CH2) b -C(=O)-(wherein b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(wherein b is 1 to 26), -C3-C8 carbocyclic-C(=O)-, -O-(C1-C8 alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C8 10 Alkylene-arylene-C(=O)-, -arylene-C1-C 10 Alkylene-C(=O)-, -C1-C 10 Alkylene-(C3-C8 carbocyclic ring)-C(=O)-, -(C3-C8 carbocyclic ring)-C1-C 10 Alkylene-C(=O)-, -C3-C8 heterocyclic-C(=O)-, -C1-C 10 Alkylene-(C3-C8 heterocycle)-C(=O)-, -(C3-C8 heterocycle)-C1-C 10 Alkylene-C(=O)-, -C1-C 10 Alkylene-NH-, C1-C 10 Heteroalkylene-NH-, -C1-C8alkylene-(CH2-O-CH2) b -NH- (wherein b is 1 to 26), -(CH2-O-CH2) b -C1-C8 alkylene-NH-(wherein b is 1 to 26), -C1-C8 alkylene-(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C(=O)-(wherein b is 1 to 26), -C1-C8 alkylene-(C(=O))-NH-(CH2-O-CH2) b -C1-C8 alkylene-C(=O)-(wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -NH- (wherein b is 1 to 26), -C1-C8 alkylene-NH-(C(=O))-(CH2-O-CH2) b -C1-C8 alkylene-NH- (wherein b is 1 to 26), -C3-C8 carbocyclic-NH-, -O-(C1-C8 alkyl)-NH-, -arylene-NH-, -C1-C8 10 Alkylene-arylene-NH-, -arylene-C1-C 10 Alkylene-NH-, -C1-C 10 Alkylene-(C3-C8 carbocyclic ring)-NH-, -(C3-C8 carbocyclic ring)-C1-C 10 Alkylene-NH-, -C3-C8 heterocyclic-NH-, -C1-C 10 Alkylene-(C3-C8 heterocycle)-NH-, -(C3-C8 heterocycle)-C1-C 10 Alkylene-NH-, -C1-C 10 Alkylene-S-, C1-C 10 Heteroalkylene-S-, -C3-C8 carbocyclic-S-, -O-(C1-C8 alkyl)-S-, -arylene-S-, -C1-C 10 Alkylene-Arylene-S-, -Arylene-C1-C 10 Alkylene-S-, -C1-C 10 Alkylene-(C3-C8 carbocyclic ring)-S-, -(C3-C8 carbocyclic ring)-C1-C 10 Alkylene-S-, -C3-C8 heterocyclic-S-, -C1-C 10 Alkylene-(C3-C8 heterocycle)-S- or -(C3-C8 heterocycle)-C1-C 10 Alkylene-S-; or The extension unit comprises a maleimide group (C1-C 10 Alkylene-C(O)-, maleimide (CH2OCH2) p2 (C1-C 10 Alkylene) C(O)-, maleimide (C1-C 10 Alkylene)(CH2OCH2) p2 C(O)- or its open ring form, wherein p2 is 1 to 26.

94. The linker intermediate or linker of claim 92, wherein the extension unit is selected from the group consisting of: as well as The wavy line represents the attachment site of the Extender unit to the Amino Acid unit, and the attachment site to the Targeting unit is on the maleimide, primary amine or alkyne functional group.

95. The linker of claim 93, having one of the following structures: wherein the Drug unit is attached to a terminal acid group, a benzyl alcohol, or wherein the wavy (≈) line indicates a site of attachment for the Drug unit.

96. The linker of claim 92, having one of the following structures: Wherein each Z is connected at * and is selected from: as well as wherein the Drug unit is optionally attached to a terminal acid group, a benzyl alcohol, or wherein the wavy (≈) line indicates the attachment site for the Drug unit.

97. The linker of any of the preceding claims, further comprising at least one Drug unit linked to the Linker subunit L2 to form a Drug-Linker.

98. The drug-linker of claim 97, wherein the drug unit is selected from a cytotoxic agent, an immunomodulator, a nucleic acid, a growth inhibitory agent, a PROTAC, a toxin, a radioisotope, and a chelating ligand.

99. The drug-linker of claim 98, wherein the Drug unit is a cytotoxic agent.

100. The drug-linker of claim 99, wherein the cytotoxic agent is selected from auristatins, maytansinoids, camptothecins, duocarmycins, and calicheamicins.

101. The drug-linker of claim 100, wherein the cytotoxic agent is auristatin.

102. The drug-linker of claim 101, wherein the cytotoxic agent is MMAE or MMAF.

103. The drug-linker of claim 100, wherein the cytotoxic agent is camptothecin.

104. The drug-linker of claim 103, wherein the cytotoxic agent is exotecan or SN-38.

105. The drug-linker of claim 104, wherein the cytotoxic agent is exotecan.

106. The drug-linker of claim 99, wherein the cytotoxic agent is calicheamicin.

107. The drug-linker of claim 99, wherein the cytotoxic agent is a maytansine compound.

108. The drug-linker of claim 107, wherein the maytansine compound is maytansine, maytansinol, or ansamycin-2.

109. The drug-linker of claim 98, wherein the Drug unit is an immunomodulator.

110. The drug-linker of claim 109, wherein the immunomodulator is selected from a TRL7 agonist, a TLR8 agonist, a STING agonist, or a RIG-I agonist.

111. The drug-linker of claim 110, wherein the immunomodulator is a TLR7 agonist.

112. The drug-linker of claim 111, wherein the TLR7 agonist is an imidazoquinoline, an imidazoquinolineamine, a thiazoquinoline, an aminoquinoline, an aminoquinazoline, a pyrido[3,2-d]pyrimidine-2,4-diamine, a pyrimidine-2,4-diamine, a 2-aminoimidazole, a 1-alkyl-1H-benzimidazol-2-amine, a tetrahydropyridopyrimidine, a heteroarothiadiazide-2,2-dioxide, a benzonaphthyridine, a guanosine analog, an adenosine analog, a thymidine homopolymer, ssRNA, CpG-A, PolyG10 or PolyG3.

113. The drug-linker of claim 110, wherein the immunomodulator is a TLR8 agonist.

114. The drug-linker of claim 113, wherein the TLR8 agonist is selected from imidazoquinoline, thiazoquinoline, aminoquinoline, aminoquinazoline, pyrido[3,2-d]pyrimidine-2,4-diamine, pyrimidine-2,4-diamine, 2-aminoimidazole, 1-alkyl-1H-benzimidazol-2-amine, tetrahydropyridopyrimidine or ssRNA.

115. The drug-linker of claim 110, wherein the immunomodulator is a STING agonist.

116. The drug-linker of claim 110, wherein the immunomodulator is a RIG-I agonist.

117. The drug-linker of claim 116, wherein the RIG-I agonist is selected from KIN1148, SB-9200, KIN700, KIN600, KIN500, KIN100, KIN101, KIN400 and KIN2000.

118. The drug-linker of claim 98, wherein the Drug unit is a chelating ligand.

119. The drug-linker of claim 118, wherein the chelating ligand is selected from platinum (Pt), ruthenium (Ru), rhodium (Rh), gold (Au), silver (Ag), copper (Cu), molybdenum (Mo), titanium (Ti) or iridium (Ir); a radioactive isotope such as yttrium-88, yttrium-90, technetium-99, copper-67, rhenium-188, rhenium-186, gallium-66, gallium-67, indium-111, indium-114, indium-115, lutetium-177, strontium-89, samarium-153 and lead-212.

120. The drug-linker of claim 97, having the structure: Wherein each Z is connected at * and is selected from: as well as Wherein each Z is connected at * and is selected from: as well as 121. A conjugate comprising a targeting unit linked to the drug-linker of any one of claims 97 to 120.

122. The conjugate of claim 121, wherein the targeting unit is selected from an antibody or an antigen binding portion thereof.

123. The conjugate of claim 122, wherein the targeting unit is a monoclonal antibody, Fab, Fab', F(ab'), Fv, disulfide-bonded Fc, scFv, single domain antibody, diabody, bispecific antibody or multispecific antibody.

124. The conjugate of claim 121, wherein the targeting unit is a diabody, a DART, an anticalin, an affibody, an avimer, a DARPin, or an adnectin.

125. The conjugate of any one of claims 121 to 124, wherein the targeting unit is monospecific.

126. The conjugate of any one of claims 121 to 125, wherein the targeting unit is divalent.

127. A conjugate as described in any one of claims 121 to 124, wherein the targeting unit is bispecific.

128. The conjugate of any one of claims 121 to 127, wherein the average drug loading (p load ) is about 1 to about 8, about 2, about 4, about 6, about 8, about 10, about 12, about 14, about 16, about 3 to about 5, about 6 to about 8, or about 8 to about 16.

129. The conjugate of any one of claims 121 to 128, selected from the group consisting of: Wherein each Z is connected at * and is selected from: as well as Wherein each Z is connected at * and is selected from: as well as Where Ab is the targeting unit and n is p load .

130. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit binds a target molecule.

131. The conjugate of claim 130, wherein the target molecule is CD19, CD20, CD30, CD33, CD70, LIV-1 or EGFRv3.

132. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit is selected from the group consisting of scFv1-ScFv2, ScFv12-Fc-scFv22, IgG-scFv, DVD-Ig, triomab / quadroma, two-in-one IgG, scFv2-Fc, TandAb and scFv-HSA-scFv.

133. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit is a cancer associated antigen.

134. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit is CD19, CD20, CD30, CD33, CD38, CA125, MUC-1, prostate specific membrane antigen (PSMA), CD44 surface adhesion molecule, mesothelin (MLSN), carcinoembryonic antigen (CEA), epidermal growth factor receptor (EGFR), EGFRvIII, vascular endothelial growth factor receptor-2 (VEGFR2), high molecular weight melanoma associated antigen (HMW-MAA), MAGE-A1, IL-1 3R-a2, GD2, 1p19q, ABL1, AKT1, ALK, APC, AR, ATM, BRAF, BRCA1, BRCA2, cKIT, cMET, CSF1R, CTNNB1, FGFR1, FGFR2, FLT3, GNA1 1. GNAQ, GNAS, HRAS, IDH1, IDH2, JAK2, KDR(VEGFR2), KRAS, MGMT, MGMT-Me, MLH1, MPL, NOTCH1, NRAS, PDGFRA, Pgp, PIK3CA, P R, PTEN, RET, RRM1, SMO, SPARC, TLE3, TOP2A, TOPO1, TP53, TS, TUBB3, VHL, CDH1, ERBB4, FBXW7, HNF1A, JAK3, NPM1, PTPN11, RB1, SMAD4, SMARCB1, STK1, MLH1, MSH2, MSH6, PMS2, ROS1, ERCC1, 5T4(TPBG), B7-H3, CCR7, CD105, CD22, CD46, CD47, CD56, C D70, CD71, CD79b, CDH6, CLDN6, CLDN18.2, CLEC12A, DLL3, DR5, ERBB3 (HER3), EPCAM, FOLR1, IGF1R, IL2RA (CD25), IL3RA, ITGB6, LIV-1, LRRC15, mesothelin (MSLN), NaPi2b (SLC34A2), adhesion protein-4, PTK7, ROR1, SEZ6, SLC44A4, SLITRK6, tissue factor (TF), TROP2 or B7-H4.

135. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit is an antibody or a fragment thereof, including rituximab Trastuzumab Pertuzumab Bevacizumab Ranibizumab Cetuximab Alemtuzumab Panitumumab Ibritumomab Tositumomab Ipilimumab, zalutumumab, daratumumab, fentolimumab, ramucirumab, galiximab, fatutumumab, oreluzumab, ofatumumab tositumumab, ibritumomab tiuxetan, CD20 antibody 2F2 (HuMax-CD20), 7D8, IgM2C6, IgG12C6, 11B8, B1, 2H7, LT20, 1FS or AT80, daclizumab or anti-LHRH receptor antibodies, including clones A9E4, F1G4, AT2G7, GNRH03 or GNRHR2.

136. The conjugate of claim 121, wherein the targeting unit is antibody F131 and the drug-linker is LD038.

137. The conjugate of any one of claims 121, 128 or 129, wherein the targeting unit is an antibody, comprising: A heavy chain variable (VH) region and a light chain variable (VL) region, the VH region comprising complementary determining regions HCDR1, HCDR2 and HCDR3 located in the heavy chain variable region framework region, the VL region comprising LCDR1, LCDR and LCDR3 located in the light chain variable region framework region, the VH and VL CDRs having an amino acid sequence selected from the group of amino acid sequences listed below: (a) SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34 and SEQ ID NO:35, respectively; and (b) are SEQ ID NO: 36, SEQ ID NO: 31, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39 and SEQ ID NO: 40, respectively.

138. conjugate as claimed in claim 137, wherein said VH and VL districts have amino acid sequences selected from the amino acid sequence pairs listed below: SEQ ID NO:26 and SEQ ID NO:27, respectively; and wherein the heavy and light chain framework regions are optionally modified by 1 to 8 amino acid substitutions, deletions or insertions in the framework regions.

139. The conjugate of claim 137, wherein the antibody is F131 and the drug-linker is LD038.

140. A conjugate comprising a targeting unit linked to a drug-linker, wherein the targeting unit is antibody F131 and the drug-linker is LD038.

141. A pharmaceutical composition comprising the conjugate of any one of claims 121 to 140 and a pharmaceutically acceptable carrier.

142. Use of a conjugate as described in any one of claims 121 to 140 or a pharmaceutical composition as described in claim 141 for preparing a medicament for treating a subject suffering from cancer or an autoimmune disease, wherein the conjugate binds to a target antigen associated with the cancer or autoimmune disease.

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